People with multiple sclerosis (MS) often present with cognitive deficits that cannot fully be attributed to focal brain alterations. Whole-brain network changes show stronger relations, but MS network insights have mostly focused on either structural or functional (single-layer) networks, while recent work has shown the importance of multilayer frontoparietal network integration for cognition. Here, we explored the cognitive relevance of multilayer integration of the frontoparietal network in relapsing-remitting MS (n=780) using diffusion and resting-state functional MRI. Cognitive relations were first assessed for nodal multilayer eigenvector centrality, averaged over frontoparietal network nodes as a measure of integration; and post-hoc for mean eccentricity for both single-layers and the multilayer.

Higher multilayer frontoparietal network centrality was associated with worse SDMT performance (β = −0.117, p = 0.005). Mean eccentricity of single-layer diffusion (β = −0.123, p < 0.001) and multilayer networks (β = 0.085, p = 0.018) were associated with cognition. However, results could not be replicated using a different anatomical parcellation.

This study showed that cognition in MS is related to multilayer network parameters. Nevertheless, correlations were weak and atlas-specific, suggesting that a binary structure-function multilayer network approach is not particularly relevant as a correlate of cognition in MS.

FB: Steering committee and iDMC member for Biogen, Merck, Roche, EISAI. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Novartis, Merck, Biogen, GE, Roche. Co-founder and share-holder of Queen Square Analytics LTD. AB has received speaker honoraria and/or compensation for travel grant and consulting service from Biogen, Merck, Genzyme, Novartis, Alexion, Amgen, UCB, Coloplast and Roche. AC is supported by EUROSTAR E!113682 HORIZON2020 and received speaker honoraria from Novartis and Roche. MC received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. OC is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. SC received travel support and speaker honoraria from Merck and is supported by Rosetrees Trust (MS632; PGL21/10079) RC was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria/travel support from Roche, Merck Serono, UCB, Sanofi-Genzyme, Alexion, Novartis, and Janssen, and received a research grant from the Italian Ministry of University and Research. CE received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla MAF has received speaker honoraria from Merck. CG: The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of Cristina Granziera, have received the following fees which were used exclusively for ( research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, biogen and Roche. EAH received honoraria for advisory board activity from Sanofi-Genzyme, and his department has received honoraria for lecturing from Biogen and Merck. SL received speaker honoraria from Sanofi, Biogen, Bristol Myers Squibb, Novartis and Merck. SM received speaking honoraria from UCB, and travel grants from Sanofi, Merck, Alexion, UCB and Roche. MM received research funding from MUR PNRR Extended Partnership (MNESYS no. PE00000006, and DHEAL-COM no. PNC-E3-2022-23683267), ECTRIMS-MAGNIMS, UK MS Society, e Merck; salary as editorial board member from Neurology (AAN, MN, USA), and Multiple Sclerosis Journal (Sage, UK); and honoraria from Abbvie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. JP has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Argenx, Roche, Medimmune, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019-2021. She acknowledges partial funding to the trust by Highly specialised services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee and chairman of the NHSE neuroimmunology patient pathway and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation. DP is a member of the advisory board for Cognition and MS for Novartis and received speaking honoraria from Biogen, Novartis, MedAhead and Bristol-Myers Squibb. GP received research grants from ECTRIMS, MAGNIMS, and ESNR MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders; and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal MMS serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. AT has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis. He is co-editor for Multiple Sclerosis Journal, an associate editor for Frontiers in Neurology - Neuro-ophthalmology section and on the editorial board for Neurology. He has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). PV received speaker honoraria from Biogen Idec. The remaining authors report no competing interests. AB has received speaker honoraria and/or compensation for travel grant and consulting service from Biogen, Merck, Genzyme, Novartis, Alexion, Amgen, UCB, Coloplast and Roche. AC is supported by EUROSTAR E!113682 HORIZON2020 and received speaker honoraria from Novartis and Roche. MC received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. OC is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. SC received travel support and speaker honoraria from Merck and is supported by Rosetrees Trust (MS632; PGL21/10079) RC was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria/travel support from Roche, Merck Serono, UCB, Sanofi-Genzyme, Alexion, Novartis, and Janssen, and received a research grant from the Italian Ministry of University and Research. CE received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi- Aventis. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla MAF has received speaker honoraria from Merck. CG: The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of Cristina Granziera, have received the following fees which were used exclusively for ( research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, biogen and Roche. EAH received honoraria for advisory board activity from Sanofi-Genzyme, and his department has received honoraria for lecturing from Biogen and Merck. SL received speaker honoraria from Sanofi, Biogen, Bristol Myers Squibb, Novartis and Merck. SM received speaking honoraria from UCB, and travel grants from Sanofi, Merck, Alexion, UCB and Roche. MM received research funding from MUR PNRR Extended Partnership (MNESYS no. PE00000006, and DHEAL-COM no. PNC-E3-2022-23683267), ECTRIMS-MAGNIMS, UK MS Society, e Merck; salary as editorial board member from Neurology (AAN, MN, USA), and Multiple Sclerosis Journal (Sage, UK); and honoraria from Abbvie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. JP has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Argenx, Roche, Medimmune, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019-2021. She acknowledges partial funding to the trust by Highly specialised services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee and chairman of the NHSE neuroimmunology patient pathway and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation. DP is a member of the advisory board for Cognition and MS for Novartis and received speaking honoraria from Biogen, Novartis, MedAhead and Bristol-Myers Squibb. GP received research grants from ECTRIMS, MAGNIMS, and ESNR MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders; and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal MMS serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. AT has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis. He is co-editor for Multiple Sclerosis Journal, an associate editor for Frontiers in Neurology Neuro-ophthalmology section and on the editorial board for Neurology. He has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). PV received speaker honoraria from Biogen Idec. The remaining authors report no competing interests. AB has received speaker honoraria and/or compensation for travel grant and consulting service from Biogen, Merck, Genzyme, Novartis, Alexion, Amgen, UCB, Coloplast and Roche. AC is supported by EUROSTAR E!113682 HORIZON2020 and received speaker honoraria from Novartis and Roche. MC received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. OC is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. SC received travel support and speaker honoraria from Merck and is supported by Rosetrees Trust (MS632; PGL21/10079) RC was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria/travel support from Roche, Merck Serono, UCB, Sanofi-Genzyme, Alexion, Novartis, and Janssen, and received a research grant from the Italian Ministry of University and Research. CE received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla MAF has received speaker honoraria from Merck. CG: The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of Cristina Granziera, have received the following fees which were used exclusively for ( research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, biogen and Roche. EAH received honoraria for advisory board activity from Sanofi-Genzyme, and his department has received honoraria for lecturing from Biogen and Merck. SL received speaker honoraria from Sanofi, Biogen, Bristol Myers Squibb, Novartis and Merck. SM received speaking honoraria from UCB, and travel grants from Sanofi, Merck, Alexion, UCB and Roche. MM received research funding from MUR PNRR Extended Partnership (MNESYS no. PE00000006, and DHEAL-COM no. PNC-E3-2022-23683267), ECTRIMS-MAGNIMS, UK MS Society, e Merck; salary as editorial board member from Neurology (AAN, MN, USA), and Multiple Sclerosis Journal (Sage, UK); and honoraria from Abbvie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. JP has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Argenx, Roche, Medimmune, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019-2021. She acknowledges partial funding to the trust by Highly specialised services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee and chairman of the NHSE neuroimmunology patient pathway and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation. DP is a member of the advisory board for Cognition and MS for Novartis and received speaking honoraria from Biogen, Novartis, MedAhead and Bristol-Myers Squibb. GP received research grants from ECTRIMS, MAGNIMS, and ESNR MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders; and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal MMS serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. AT has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis. He is co-editor for Multiple Sclerosis Journal, an associate editor for Frontiers in Neurology - Neuro-ophthalmology section and on the editorial board for Neurology. He has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). PV received speaker honoraria from Biogen Idec. The remaining authors report no competing interests. AB has received speaker honoraria and/or compensation for travel grant and consulting service from Biogen, Merck, Genzyme, Novartis, Alexion, Amgen, UCB, Coloplast and Roche. AC is supported by EUROSTAR E!113682 HORIZON2020 and received speaker honoraria from Novartis and Roche. MC received speaker honoraria from Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, and Roche and receives research support from the Progressive MS Alliance and Italian Minister of Health. OC is an NIHR Research Professor (RP-2017-08-ST2-004); acts as a consultant for Biogen, Merck, Novartis, Roche, and Teva; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. SC received travel support and speaker honoraria from Merck and is supported by Rosetrees Trust (MS632; PGL21/10079) RC was awarded a MAGNIMS-ECTRIMS fellowship in 2019; she received speaker honoraria/travel support from Roche, Merck Serono, UCB, Sanofi-Genzyme, Alexion, Novartis, and Janssen, and received a research grant from the Italian Ministry of University and Research. CE received travel funding and speaker honoraria from Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, Genzyme and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis, Shire; received research support from Merck Serono, Biogen Idec, and Teva Pharmaceutical Industries Ltd./Sanofi-Aventis; and serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Genzyme, Roche, and Teva Pharmaceutical Industries Ltd./Sanofi- Aventis. MF is Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla MAF has received speaker honoraria from Merck. CG: The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of Cristina Granziera, have received the following fees which were used exclusively for ( research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, biogen and Roche. EAH received honoraria for advisory board activity from Sanofi-Genzyme, and his department has received honoraria for lecturing from Biogen and Merck. SL received speaker honoraria from Sanofi, Biogen, Bristol Myers Squibb, Novartis and Merck. SM received speaking honoraria from UCB, and travel grants from Sanofi, Merck, Alexion, UCB and Roche. MM received research funding from MUR PNRR Extended Partnership (MNESYS no. PE00000006, and DHEAL-COM no. PNC-E3-2022-23683267), ECTRIMS-MAGNIMS, UK MS Society, e Merck; salary as editorial board member from Neurology (AAN, MN, USA), and Multiple Sclerosis Journal (Sage, UK); and honoraria from Abbvie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. JP has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, Vitaccess, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Argenx, Roche, Medimmune, Amplo biotechnology. Patent ref P37347WO and licence agreement Numares multimarker MS diagnostics Shares in AstraZenica. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019-2021. She acknowledges partial funding to the trust by Highly specialised services NHS England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackon Foundation Charity and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee and chairman of the NHSE neuroimmunology patient pathway and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation. DP is a member of the advisory board for Cognition and MS for Novartis and received speaking honoraria from Biogen, Novartis, MedAhead and Bristol-Myers Squibb. GP received research grants from ECTRIMS, MAGNIMS, and ESNR MAR received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders; and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal MMS serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck. AT has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis. He is co-editor for Multiple Sclerosis Journal, an associate editor for Frontiers in Neurology Neuro-ophthalmology section and on the editorial board for Neurology. He has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). PV received speaker honoraria from Biogen Idec. The remaining authors report no competing interests.

G.P. was supported by the ECTRIMS-MAGNIMS Research Fellowship Programme (2020). F.P. and B.K. are supported by the UK National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at UCLH and UCL. A.C. is supported by EUROSTAR E!113682 HORIZON2020. Sa.Co. is supported by a Rosetrees Trust Grant (PGL21/10079). M.A.F. is supported by a grant from the MRC (MR/S026088/1). L.D. Is supported by the Dutch Research Council (NWO, Vidi 198.015). The study was supported by grants from The Research Council of Norway (NFR, grant number 240102) and the South-Eastern Health Authorities of Norway (grant number 257955).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Committee of University College London gave approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data from patients are controlled by the respective centers (listed in Supplementary Table 1) and therefore are not publicly available. Request to access raw data should be forwarded to data controllers via the corresponding author. Derived data supporting the findings of this study can be requested by qualified investigators from the corresponding author.